J. Exp. Med., Volume 187, Number 5, March 2, 1998 663-674

B Lymphocytes Differentially Use the Rel and Nuclear Factor B1 (NF-B1) Transcription Factors to Regulate Cell Cycle Progression and Apoptosis in Quiescent and Mitogen-activated Cells

By Raelene J. Grumont,^* Ian J. Rourke,^* Lorraine A. O'Reilly,^* Andreas Strasser,^* Kensuke Miyake, William Sha,^§ and Steve Gerondakis^*

From ^* The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia; the  Department of Immunology, Saga Medical School, Nabeshima, Saga 849, Japan; and the ^§ University of California, Berkeley, California 94720

Rel and nuclear factor (NF)-B1, two members of the Rel/NF-B transcription factor family, are essential for mitogen-induced B cell proliferation. Using mice with inactivated Rel or NF-B1 genes, we show that these transcription factors differentially regulate cell cycle progression and apoptosis in B lymphocytes. Consistent with an increased rate of mature B cell turnover in naive nfkb1^/ mice, the level of apoptosis in cultures of quiescent nfkb1^/, but not c-rel^/, B cells is higher. The failure of c-rel^/ or nfkb1^/ B cells to proliferate in response to particular mitogens coincides with a cell cycle block early in G1 and elevated cell death. Expression of a bcl-2 transgene prevents apoptosis in resting and activated c-rel^/ and nfkb1^/ B cells, but does not overcome the block in cell cycle progression, suggesting that the impaired proliferation is not simply a consequence of apoptosis and that Rel/NF-B proteins regulate cell survival and cell cycle control through independent mechanisms. In contrast to certain B lymphoma cell lines in which mitogen-induced cell death can result from Rel/NF-B-dependent downregulation of c-myc, expression of c-myc is normal in resting and stimulated c-rel^/ B cells, indicating that target gene(s) regulated by Rel that are important for preventing apoptosis may differ in normal and immortalized B cells. Collectively, these results are the first to demonstrate that in normal B cells, NF-B1 regulates survival of cells in G0, whereas mitogenic activation induced by distinct stimuli requires different Rel/NF-B factors to control cell cycle progression and prevent apoptosis.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Krug, L. T., Collins, C. M., Gargano, L. M., Speck, S. H. (2009). NF-{kappa}B p50 Plays Distinct Roles in the Establishment and Control of Murine Gammaherpesvirus 68 Latency. J. Virol. 83: 4732-4748 [Abstract] [Full Text]  
• Banerjee, A., Grumont, R., Gugasyan, R., White, C., Strasser, A., Gerondakis, S. (2008). NF-{kappa}B1 and c-Rel cooperate to promote the survival of TLR4-activated B cells by neutralizing Bim via distinct mechanisms. Blood 112: 5063-5073 [Abstract] [Full Text]  
• Khiem, D., Cyster, J. G., Schwarz, J. J., Black, B. L. (2008). A p38 MAPK-MEF2C pathway regulates B-cell proliferation. Proc. Natl. Acad. Sci. USA 105: 17067-17072 [Abstract] [Full Text]  
• Gupta, N., Delrow, J., Drawid, A., Sengupta, A. M., Fan, G., Gelinas, C. (2008). Repression of B-Cell Linker (BLNK) and B-Cell Adaptor for Phosphoinositide 3-Kinase (BCAP) Is Important for Lymphocyte Transformation by Rel Proteins. Cancer Res. 68: 808-814 [Abstract] [Full Text]  
• Souto-Carneiro, M. M., Fritsch, R., Sepulveda, N., Lagareiro, M. J., Morgado, N., Longo, N. S., Lipsky, P. E. (2008). The NF-{kappa}B Canonical Pathway Is Involved in the Control of the Exonucleolytic Processing of Coding Ends during V(D)J Recombination. J. Immunol. 180: 1040-1049 [Abstract] [Full Text]  
• Yang, C. H., Murti, A., Pfeffer, L. M. (2005). Interferon Induces NF-{kappa}B-inducing Kinase/Tumor Necrosis Factor Receptor-associated Factor-dependent NF-{kappa}B Activation to Promote Cell Survival. J. Biol. Chem. 280: 31530-31536 [Abstract] [Full Text]  
• Hebeis, B., Vigorito, E., Kovesdi, D., Turner, M. (2005). Vav proteins are required for B-lymphocyte responses to LPS. Blood 106: 635-640 [Abstract] [Full Text]  
• Brambilla, R., Bracchi-Ricard, V., Hu, W.-H., Frydel, B., Bramwell, A., Karmally, S., Green, E. J., Bethea, J. R. (2005). Inhibition of astroglial nuclear factor {kappa}B reduces inflammation and improves functional recovery after spinal cord injury. JEM 202: 145-156 [Abstract] [Full Text]  
• Petlickovski, A., Laurenti, L., Li, X., Marietti, S., Chiusolo, P., Sica, S., Leone, G., Efremov, D. G. (2005). Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. Blood 105: 4820-4827 [Abstract] [Full Text]  
• Nakata, S., Matsumura, I., Tanaka, H., Ezoe, S., Satoh, Y., Ishikawa, J., Era, T., Kanakura, Y. (2004). NF-{kappa}B Family Proteins Participate in Multiple Steps of Hematopoiesis through Elimination of Reactive Oxygen Species. J. Biol. Chem. 279: 55578-55586 [Abstract] [Full Text]  
• Zarnegar, B., He, J. Q., Oganesyan, G., Hoffmann, A., Baltimore, D., Cheng, G. (2004). Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-{kappa}B activation pathways. Proc. Natl. Acad. Sci. USA 101: 8108-8113 [Abstract] [Full Text]  
• Piatelli, M. J., Wardle, C., Blois, J., Doughty, C., Schram, B. R., Rothstein, T. L., Chiles, T. C. (2004). Phosphatidylinositol 3-Kinase-Dependent Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase 1/2 and NF-{kappa}B Signaling Pathways Are Required for B Cell Antigen Receptor-Mediated Cyclin D2 Induction in Mature B Cells. J. Immunol. 172: 2753-2762 [Abstract] [Full Text]  
• Kanters, E., Gijbels, M. J.J., van der Made, I., Vergouwe, M. N., Heeringa, P., Kraal, G., Hofker, M. H., de Winther, M. P. J. (2004). Hematopoietic NF-{kappa}B1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype. Blood 103: 934-940 [Abstract] [Full Text]  
• Bernard, D., Gosselin, K., Monte, D., Vercamer, C., Bouali, F., Pourtier, A., Vandenbunder, B., Abbadie, C. (2004). Involvement of Rel/Nuclear Factor-{kappa}B Transcription Factors in Keratinocyte Senescence. Cancer Res. 64: 472-481 [Abstract] [Full Text]  
• Prendes, M., Zheng, Y., Beg, A. A. (2003). Regulation of Developing B Cell Survival by RelA-Containing NF-{kappa}B Complexes. J. Immunol. 171: 3963-3969 [Abstract] [Full Text]  
• De Bosscher, K., Vanden Berghe, W., Haegeman, G. (2003). The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression. Endocr. Rev. 24: 488-522 [Abstract] [Full Text]  
• Hatada, E. N., Do, R. K. G., Orlofsky, A., Liou, H.-C., Prystowsky, M., MacLennan, I. C. M., Caamano, J., Chen-Kiang, S. (2003). NF-{kappa}B1 p50 Is Required for BLyS Attenuation of Apoptosis but Dispensable for Processing of NF-{kappa}B2 p100 to p52 in Quiescent Mature B Cells. J. Immunol. 171: 761-768 [Abstract] [Full Text]  
• Kim, S., La Motte-Mohs, R. N. A., Rudolph, D., Zuniga-Pflucker, J. C., Mak, T. W. (2003). The role of nuclear factor-kappa B essential modulator (NEMO) in B cell development and survival. Proc. Natl. Acad. Sci. USA 100: 1203-1208 [Abstract] [Full Text]  
• Kantengwa, S., Jornot, L., Devenoges, C., Nicod, L. P. (2003). Superoxide Anions Induce the Maturation of Human Dendritic Cells. Am. J. Respir. Crit. Care Med. 167: 431-437 [Abstract] [Full Text]  
• Schmidt, C. S., Liu, J., Zhang, T., Song, H. Y., Sandusky, G., Mintze, K., Benschop, R. J., Glasebrook, A., Yang, D. D., Na, S. (2003). Enhanced B Cell Expansion, Survival, and Humoral Responses by Targeting Death Receptor 6. JEM 197: 51-62 [Abstract] [Full Text]  
• Cabatingan, M. S., Schmidt, M. R., Sen, R., Woodland, R. T. (2002). Naive B Lymphocytes Undergo Homeostatic Proliferation in Response to B Cell Deficit. J. Immunol. 169: 6795-6805 [Abstract] [Full Text]  
• O'Keeffe, M., Hochrein, H., Vremec, D., Caminschi, I., Miller, J. L., Anders, E. M., Wu, L., Lahoud, M. H., Henri, S., Scott, B., Hertzog, P., Tatarczuch, L., Shortman, K. (2002). Mouse Plasmacytoid Cells: Long-lived Cells, Heterogeneous in Surface Phenotype and Function, that Differentiate Into CD8+ Dendritic Cells Only after Microbial Stimulus. JEM 196: 1307-1319 [Abstract] [Full Text]  
• Ursini-Siegel, J., Zhang, W., Altmeyer, A., Hatada, E. N., Do, R. K. G., Yagita, H., Chen-Kiang, S. (2002). TRAIL/Apo-2 Ligand Induces Primary Plasma Cell Apoptosis. J. Immunol. 169: 5505-5513 [Abstract] [Full Text]  
• Pasparakis, M., Schmidt-Supprian, M., Rajewsky, K. (2002). I{kappa}B Kinase Signaling Is Essential for Maintenance of Mature B Cells. JEM 196: 743-752 [Abstract] [Full Text]  
• Kaku, H., Horikawa, K., Obata, Y., Kato, I., Okamoto, H., Sakaguchi, N., Gerondakis, S., Takatsu, K. (2002). NF-{kappa}B is required for CD38-mediated induction of C{gamma}1 germline transcripts in murine B lymphocytes. Int Immunol 14: 1055-1064 [Abstract] [Full Text]  
• Nakamura, Y., Grumont, R. J., Gerondakis, S. (2002). NF-{kappa}B1 Can Inhibit v-Abl-Induced Lymphoid Transformation by Functioning as a Negative Regulator of Cyclin D1 Expression. Mol. Cell. Biol. 22: 5563-5574 [Abstract] [Full Text]  
• Hsia, C. Y., Cheng, S., Owyang, A. M., Dowdy, S. F., Liou, H.-C. (2002). c-Rel regulation of the cell cycle in primary mouse B lymphocytes. Int Immunol 14: 905-916 [Abstract] [Full Text]  
• Caamano, J., Hunter, C. A. (2002). NF-{kappa}B Family of Transcription Factors: Central Regulators of Innate and Adaptive Immune Functions. Clin. Microbiol. Rev. 15: 414-429 [Abstract] [Full Text]  
• Mitsiades, N., Mitsiades, C. S., Poulaki, V., Chauhan, D., Richardson, P. G., Hideshima, T., Munshi, N., Treon, S. P., Anderson, K. C. (2002). Biologic sequelae of nuclear factor-kappa B blockade in multiple myeloma: therapeutic applications. Blood 99: 4079-4086 [Abstract] [Full Text]  
• Pohl, T., Gugasyan, R., Grumont, R. J., Strasser, A., Metcalf, D., Tarlinton, D., Sha, W., Baltimore, D., Gerondakis, S. (2002). The combined absence of NF-kappa B1 and c-Rel reveals that overlapping roles for these transcription factors in the B cell lineage are restricted to the activation and function of mature cells. Proc. Natl. Acad. Sci. USA 99: 4514-4519 [Abstract] [Full Text]  
• Ren, H., Schmalstieg, A., Yuan, D., Gaynor, R. B. (2002). I-{kappa}B Kinase {beta} Is Critical for B Cell Proliferation and Antibody Response. J. Immunol. 168: 577-587 [Abstract] [Full Text]  
• Davis, R. E., Brown, K. D., Siebenlist, U., Staudt, L. M. (2001). Constitutive Nuclear Factor {kappa}B Activity Is Required for Survival of Activated B Cell-like Diffuse Large B Cell Lymphoma Cells. JEM 194: 1861-1874 [Abstract] [Full Text]  
• Owyang, A. M., Tumang, J. R., Schram, B. R., Hsia, C. Y., Behrens, T. W., Rothstein, T. L., Liou, H.-C. (2001). c-Rel Is Required for the Protection of B Cells from Antigen Receptor-Mediated, But Not Fas-Mediated, Apoptosis. J. Immunol. 167: 4948-4956 [Abstract] [Full Text]  
• Guzman, M. L., Neering, S. J., Upchurch, D., Grimes, B., Howard, D. S., Rizzieri, D. A., Luger, S. M., Jordan, C. T. (2001). Nuclear factor-{kappa}B is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98: 2301-2307 [Abstract] [Full Text]  
• Kimura, K., Markowski, M., Bowen, C., Gelmann, E. P. (2001). Androgen Blocks Apoptosis of Hormone-dependent Prostate Cancer Cells. Cancer Res. 61: 5611-5618 [Abstract] [Full Text]  
• GENCAY, M., RÜDIGER, J. J., TAMM, M., SOLÉR, M., PERRUCHOUD, A. P., ROTH, M. (2001). Increased Frequency of Chlamydia pneumoniae Antibodies in Patients with Asthma. Am. J. Respir. Crit. Care Med. 163: 1097-1100 [Abstract] [Full Text]  
• Kaisho, T., Takeda, K., Tsujimura, T., Kawai, T., Nomura, F., Terada, N., Akira, S. (2001). I{{kappa}}B Kinase {{alpha}} Is Essential for Mature B Cell Development and Function. JEM 193: 417-426 [Abstract] [Full Text]  
• Chen, C.-L., Singh, N., Yull, F. E., Strayhorn, D., Van Kaer, L., Kerr, L. D. (2000). Lymphocytes Lacking I{kappa}B-{alpha} Develop Normally, But Have Selective Defects in Proliferation and Function. J. Immunol. 165: 5418-5427 [Abstract] [Full Text]  
• Cariappa, A., Liou, H.-C., Horwitz, B. H., Pillai, S. (2000). Nuclear Factor {kappa}B Is Required for the Development of Marginal Zone B Lymphocytes. JEM 192: 1175-1182 [Abstract] [Full Text]  
• Keller, S. A., Schattner, E. J., Cesarman, E. (2000). Inhibition of NF-kappa B induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 96: 2537-2542 [Abstract] [Full Text]  
• Do, R. K.G., Hatada, E., Lee, H., Tourigny, M. R., Hilbert, D., Chen-Kiang, S. (2000). Attenuation of Apoptosis Underlies B Lymphocyte Stimulator Enhancement of Humoral Immune Response. JEM 192: 953-964 [Abstract] [Full Text]  
• Seitz, C. S., Deng, H., Hinata, K., Lin, Q., Khavari, P. A. (2000). Nuclear Factor {{kappa}}B Subunits Induce Epithelial Cell Growth Arrest. Cancer Res. 60: 4085-4092 [Abstract] [Full Text]  
• Petro, J. B., Rahman, S.M. J., Ballard, D. W., Khan, W. N. (2000). Bruton's Tyrosine Kinase Is Required for Activation of I{kappa}B Kinase and Nuclear Factor {kappa}B in Response to B Cell Receptor Engagement. JEM 191: 1745-1754 [Abstract] [Full Text]  
• Grumont, R. J., Gerondakis, S. (2000). Rel Induces Interferon Regulatory Factor 4 (IRF-4) Expression in Lymphocytes: Modulation of Interferon-regulated Gene Expression by Rel/Nuclear Factor {kappa}B. JEM 191: 1281-1292 [Abstract] [Full Text]  
• Grossmann, M., Metcalf, D., Merryfull, J., Beg, A., Baltimore, D., Gerondakis, S. (1999). The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc. Natl. Acad. Sci. USA 96: 11848-11853 [Abstract] [Full Text]  
• Tuscano, J. M., Riva, A., Toscano, S. N., Tedder, T. F., Kehrl, J. H. (1999). CD22 Cross-Linking Generates B-Cell Antigen Receptor-Independent Signals That Activate the JNK/SAPK Signaling Cascade. Blood 94: 1382-1392 [Abstract] [Full Text]  
• Guttridge, D. C., Albanese, C., Reuther, J. Y., Pestell, R. G., Baldwin, A. S. Jr. (1999). NF-kappa B Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1. Mol. Cell. Biol. 19: 5785-5799 [Abstract] [Full Text]  
• Doerre, S., Corley, R. B. (1999). Constitutive Nuclear Translocation of NF-{kappa}B in B Cells in the Absence of I{kappa}B Degradation. J. Immunol. 163: 269-277 [Abstract] [Full Text]  
• Erl, W., Hansson, G. K., de Martin, R., Draude, G., Weber, K. S. C., Weber, C. (1999). Nuclear Factor-{kappa}B Regulates Induction of Apoptosis and Inhibitor of Apoptosis Protein-1 Expression in Vascular Smooth Muscle Cells. Circ. Res. 84: 668-677 [Abstract] [Full Text]  
• Grumont, R. J., Rourke, I. J., Gerondakis, S. (1999). Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev. 13: 400-411 [Abstract] [Full Text]  
• Rescigno, M., Martino, M., Sutherland, C. L., Gold, M. R., Ricciardi-Castagnoli, P. (1998). Dendritic Cell Survival and Maturation Are Regulated by Different Signaling Pathways. JEM 188: 2175-2180 [Abstract] [Full Text]  
• Abdouh, M., Storring, J. M., Riad, M., Paquette, Y., Albert, P. R., Drobetsky, E., Kouassi, E. (2001). Transcriptional Mechanisms for Induction of 5-HT1A Receptor mRNA and Protein in Activated B and T Lymphocytes. J. Biol. Chem. 276: 4382-4388 [Abstract] [Full Text]  
• Petro, J. B., Khan, W. N. (2001). Phospholipase C-gamma 2 Couples Bruton's Tyrosine Kinase to the NF-kappa B Signaling Pathway in B Lymphocytes. J. Biol. Chem. 276: 1715-1719 [Abstract] [Full Text]  
• Cahir-McFarland, E. D., Davidson, D. M., Schauer, S. L., Duong, J., Kieff, E. (2000). NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells. Proc. Natl. Acad. Sci. USA 97: 6055-6060 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS